3-oxo-6-heteroaryl-2-phenyl-2,3-dihydropyridazine-4-carboxamides

1. A compound of formula (I):

wherein

X is N, Y is CR 3 , and Z is CH, or

X is CH, Y is N, and Z is CH, or

Z and Y are N, X is CH, and R 2 is trifluoromethyl;

R 1 is C 2 -C 8 -hydroxyalkyl, wherein said C 2 -C 8 -hydroxyalkyl groups are optionally substituted once with R 7 and optionally one to three times with halogen, or C 3 -C 6 -cycloalkyl substituted once with hydroxy or C 1 -C 3 -hydroxyalkyl and optionally one to three times with halogen, or

(C 3 -C 6 -cycloalkyl substituted once with hydroxy)-C 1 -C 4 -alkyl, or

4- to 6-membered heterocycloalkyl substituted once with hydroxy or

C 1 -C 3 -hydroxyalkyl and optionally one to three times with halogen, or

(4- to 6-membered heterocycloalkyl substituted once with hydroxy)-C 1 -C 4 -alkyl;

R 2 is chloro, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, or —NR 8 R 9 ;

R 3 is hydrogen, halogen, or methyl;

R 4 is hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, halogen, or cyano;

R 5 is hydrogen or halogen;

R 6 is hydrogen or halogen;

R 7 is C 1 -C 4 -alkoxy, C 3 -C 6 -cycloalkyl, 4- to 6-membered heterocycloalkyl, —CO 2 —R 10 , —CO—NR 8 R 9 , cyano, or —NR 8 R 9 ;

R 8 and R 9 are the same or different and are, independently from each other, hydrogen or C 1 -C 3 -alkyl, or

together with the nitrogen atom to which they are attached form a 4- to 6-membered nitrogen containing heterocyclic ring, said ring optionally containing one additional heteroatom selected from the group consisting of O, S, NH, and NR a in which R a is a C 1 -C 4 -alkyl group; and

R 10 is hydrogen or C 1 -C 4 -alkyl; or

a polymorph, an enantiomer, a diastereomer, a racemate, a tautomer, an N-oxide, a hydrate, or a solvate, a physiologically acceptable salt, a solvate of a physiologically acceptable salt thereof, or a mixture of any of the foregoing.

2. The compound according to claim 1 , wherein:

R 1 is C 2 -C 6 -hydroxyalkyl, wherein said C 2 -C 6 -hydroxyalkyl groups are optionally substituted once with R 7 and optionally one to three times with fluoro or chloro, or

C 3 -C 6 -cycloalkyl substituted once with hydroxy, or

4- to 6-membered heterocycloalkyl substituted once with hydroxy;

R 2 is chloro, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy or —NR 8 R 9 ;

R 3 is hydrogen or methyl;

R 4 is hydrogen, fluoro, or chloro;

R 5 is hydrogen or fluoro;

R 6 is hydrogen or fluoro;

R 7 is methoxy, cyclopropyl, or tetrahydrofuranyl;

R 8 and R 9 are the same or different and are, independently from each other, hydrogen or methyl; or

a polymorph, an enantiomer, a diastereomer, a racemate, a tautomer, an N-oxide, a hydrate, or a solvate, a physiologically acceptable salt, a solvate of a physiologically acceptable salt thereof, or a mixture of any of the foregoing.

3. The compound according to claim 1 , wherein:

R 1 is C 3 -C 5 -hydroxyalkyl, wherein said C 3 -C 5 -hydroxyalkyl groups are optionally substituted one to three times with fluoro, or cyclopentyl substituted once with hydroxy, or tetrahydrothiophenyl substituted once with hydroxy;

R 2 is methyl, difluoromethyl, trifluoromethyl, methoxy, or —NR 8 R 9 ;

R 3 is hydrogen;

R 4 is hydrogen, fluoro, or chloro;

R 5 is hydrogen or fluoro;

R 6 is hydrogen or fluoro;

R 8 and R 9 are each methyl; or

a polymorph, an enantiomer, a diastereomer, a racemate, a tautomer, an N-oxide, a hydrate, or a solvate, a physiologically acceptable salt, a solvate of a physiologically acceptable salt thereof, or a mixture of any of the foregoing.

4. The compound according to claim 1 , which is selected from the group consisting of

2-(3,5-Difluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-3-oxo-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxamide;

2-(3-Chloro-5-fluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-3-oxo-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxamide;

2-(3,4-Difluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-3-oxo-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxamide;

2-(3-Chlorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-3-oxo-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxamide;

N-[(2S)-1-Hydroxypropan-2-yl]-3-oxo-2-phenyl-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxamide;

2-(3-Fluorophenyl)-N-[1S,2S)-2-hydroxycyclopentyl]-3-oxo-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxamide;

2-(3-Fluorophenyl)-N-[(2R)-3-hydroxy-3-methylbutan-2-yl]-3-oxo-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxamide;

2-(3-Fluorophenyl)-N-[1S,2R)-2-hydroxycyclopentyl]-3-oxo-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxamide;

2-(3-Fluorophenyl)-N-[(2S)-3-hydroxy-3-methylbutan-2-yl]-3-oxo-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxamide;

2-(3-Fluorophenyl)-N-(2-hydroxy-2-methylpropyl)-3-oxo-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxamide;

2-(3-Fluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-3-oxo-6-[2-(trifluoromethyl)pyrimidin-5-yl]-2,3-dihydropyridazine-4-carboxamide;

2-(3-Fluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-6-(5-methylpyridin-2-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide;

6-[6-(Difluoromethyl)pyridin-3-yl]-2-(3-fluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide;

2-(3-Fluorophenyl)-N-[(2S)-3-hydroxy-3-methylbutan-2-yl]-3-oxo-6-[2-(trifluoromethyl)pyrimidin-5-yl]-2,3-dihydropyridazine-4-carboxamide;

N-[(2S)-3,3-Difluoro-2-hydroxypropyl]-2-(3-fluorophenyl)-3-oxo-6-[2-(trifluoromethyl)pyrimidin-5-yl]-2,3-dihydropyridazine-4-carboxamide;

2-(3-Fluorophenyl)-N-[(2S,3S)-3-hydroxybutan-2-yl]3-oxo-6-[2-(trifluoromethyl)pyrimidin-5-yl]-2,3-dihydropyridazine-4-carboxamide;

2-(3-Fluorophenyl)-N-(2-hydroxy-2-methylpropyl)-3-oxo-6-[2-(trifluoromethyl)pyrimidin-5-yl]-2,3-dihydropyridazine-4-carboxamide;

2-(3-Fluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-3-oxo-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxamide;

6-[6-(Dimethylamino)pyridin-3-yl]-2-(3-fluorophenyl)-N-[(2R)-3-hydroxy-3-methylbutan-2-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide;

2-(3-Fluorophenyl)-N-[(2R)-3-hydroxy-3-methylbutan-2-yl]-6-(6-methoxypyridin-3-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide;

2-(3-Fluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-6-(6-methoxypyridin-3-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide;

6-[6-(Difluoromethyl)pyridin-3-yl]-2-(3-fluorophenyl)-N[(2R)-3-hydroxy-3-methylbutan-2-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide;

2-(3-Fluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-6-(6-methylpyridin-3-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide;

6-(5-Chloropyridin-2-yl)-2-(3-fluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide;

2-(3-Fluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-3-oxo-6-[5-(trifluoromethyl)pyridin-2-yl]-2,3-dihydropyridazine-4-carboxamide;

2-(3-Fluorophenyl)-N-[(3S,4R)-4-hydroxytetrahydrothiophen-3-yl]-3-oxo-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxamide;

N-[(1S)-1-Cyclopropyl-2-hydroxy-2-methylpropyl]-6-[6-(difluoromethyl)pyridin-3-yl]-2-(3-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide;

6-[6-(Difluoromethyl)pyridin-3-yl]-2-(3-fluorophenyl)-3-oxo-N-[(2R)-1,1,1-trifluoro-3-hydroxypropan-2-yl]-2,3-dihydropyridazine-4-carboxamide;

N-[(1S)-1-Cyclopropyl-2-hydroxyethyl]-6-]6-(difluoromethyl)pyridin-3-yl]-2-(3-fluorophenyl)-3-oxo-2,3-Dihydropyridazine-4-carboxamide;

6-[6-(Difluoromethyl)pyridin-3-yl]-2-(3-fluorophenyl)-N[(1S,2R)-2-hydroxycyclopentyl]-3-oxo-2,3-dihydropyridazine-4-carboxamide;

6-[6-(Difluoromethyl)pyridin-3-yl]-2-(3-fluorophenyl)-N[(1-hydroxycyclohexyl)methyl]-3-oxo-2,3-dihydropyridazine-4-carboxamide;

N-[(1S)-1-Cyano-2-hydroxyethyl]-6-[6-(difluoromethyl)pyridin-3-yl]-2-(3-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide;

6-[6-(Difluoromethyl)pyridin-3-yl]-2-(3-fluorophenyl)-N[(3S,4S)-4-hydroxyoxolan-3-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide;

6-[6-(Difluoromethyl)pyridin-3-yl]-2-(3-fluorophenyl)-N-(2-hydroxy-2-methylpropyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide;

1,5-Anhydro-2,4-dideoxy-2-[({6-[6-(difluoromethyl)pyridin-3-yl]-2-(3-fluorophenyl)-3-oxo-2,3-dihydropyridazin-4-yl}carbonyl)amino]-D-erythro-pentitol;

6-[6-(Difluoromethyl)pyridin-3-yl]-2-(3-fluorophenyl)-N-[2-hydroxy-1-(tetrahydrofuran-3-yl)ethyl]-3-oxo-2,3-dihydropyridazine-4-carboxamide;

1,5-Anhydro-2,4-dideoxy-2-[({6-[6-(difluoromethyl)pyridin-3-yl]-2-(3-fluorophenyl)-3-oxo-2,3-dihydropyridazin-4-yl}carbonyl)amino]-L-threo-pentitol;

6-[6-(Difluoromethyl)pyridin-3-yl]-2-(3-fluorophenyl)-N-[(3S,4R)-4-hydroxytetrahydrofuran-3-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide;

N-[(1S)-1-Cyano-2-hydroxyethyl]-2-(3-fluorophenyl)-3-oxo-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxamide;

1,5-Anhydro-2,4-dideoxy-2-[({2-(3-fluorophenyl)-3-oxo-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazin-4-yl}carbonyl)amino]-D-erythro-pentitol;

2-(3,5-Difluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-3-oxo-6-[5-(trifluoromethyl)pyridin-2-yl]-2,3-dihydropyridazine-4-carboxamide;

N-[(2S)-1-Hydroxypropan-2-yl]-3-oxo-2-phenyl-6-[5-(trifluoromethyl)pyridin-2-yl]-2,3-dihydropyridazine-4-carboxamide; and

2-(3,4-Difluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-3-oxo-6-[5-(trifluoromethyl)pyridin-2-yl]-2,3-dihydropyridazine-4-carboxamide; or

a polymorph, an enantiomer, a diastereomer, a racemate, a tautomer, an N-oxide, a hydrate, or a solvate, a physiologically acceptable salt, a solvate of a physiologically acceptable salt thereof, or a mixture of any of the foregoing.

5. A method of preparing a compound of formula (I) according to claim 1 , said method comprising the step of reacting an intermediate compound of formula (VII):

in which R 2 , R 4 , R 5 , R 6 , X, Y and Z are as defined for the compound of formula (I) according to claim 1 ,

with a compound of formula (VIII):

H 2 N-R 1

(VIII),

in which R 1 is as defined for the compound of formula (I) according to claim 1 , thereby giving a compound of formula (I):

in which R 1 , R 2 , R 4 , R 5 , R 6 , X, Y and Z are as defined for the compound of formula (I) according to claim 1 .

6. A pharmaceutical composition comprising a compound of formula (I) according to claim 1 , or a polymorph, an enantiomer, a diastereomer, a racemate, a tautomer, an N-oxide, a hydrate, or a solvate, a physiologically acceptable salt, a solvate of a physiologically acceptable salt thereof, or a mixture of any of the foregoing, and one or more pharmaceutically acceptable excipients.

7. A pharmaceutical combination comprising:

one or more compounds of formula (I) according to claim 1 , or a polymorph, an enantiomer, a diastereomer, a racemate, a tautomer, an N-oxide, a hydrate, or a solvate, a physiologically acceptable salt, a solvate of a physiologically acceptable salt thereof, or a mixture of any of the foregoing, and

one or more pharmaceutically active anti cancer compounds or

one or more pharmaceutically active immune checkpoint inhibitors.

8. A physiologically acceptable salt of a compound of formula (I) according to claim 1 .